Design, synthesis and in vitro antitumor evaluation of novel diaryl urea derivatives bearing sulfonamide moiety

Article abstract of DOI:10.1007/s11426-013-4903-z

A novel series of diaryl urea derivatives bearing sulfonamide moiety have been designed and synthesized. Their in vitro antitumor effect against human cancer cell lines MX-1, A375, HepG2, Ketr3 and HT-29 was screened and evaluated by the standard MTT assa

Full text of DOI:10.1007/s11426-013-4903-z

SCIENCE CHINA
Chemistry
•
ARTICLES •
Ja nd uo ai :r y1 02 . 01 10 30 7/ sV1 o1 l4. 52 6-0 1N 3 o- 4. 19 :0 13 –- 9z
doi: 10.1007/s11426-013-4903-z
Design, synthesis and in vitro antitumor evaluation of novel diaryl
urea derivatives bearing sulfonamide moiety
*
*
LUO Can, TANG Ke, LI Yan, YIN DaLi, CHEN XiaoGuang & HUANG HaiHong
Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation; Institute of Materia Medica,
Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, China
Received April 22, 2013; accepted May 22, 2013
A novel series of diaryl urea derivatives bearing sulfonamide moiety have been designed and synthesized. Their in vitro antitumor
effect against human cancer cell lines MX-1, A375, HepG2, Ketr3 and HT-29 was screened and evaluated by the standard MTT
assay with sorafenib as the positive control. Some of the compounds showed significant inhibitory activity against multiple cell
lines compared to sorafenib. In particular, 2,6-dimethyl-4-{6-[3-(4-chloro-3-(trifluoromethyl)phenyl)urea]naphthalene-
2-yl}sulfonyl morpholine (10d) was found to be the most potent against A375, HepG2 and Ketr3 with IC50 values of 0.65–0.97
mol/L, which were 5–20-fold more potent than sorafenib. Compound 10d emerged as a valuable lead for further optimization.
diaryl urea derivatives, sulfonamide, sorafenib, antitumor activity
1
Introduction
phenyl ring between the urea moiety and the ether bond
interacts with kinase through hydrophobic interaction
fragment C), and the N-methyl-4-picolinamide (fragment D)
binds to the hinge region of kinase which is highly mobile
10, 11]. This motif (frogment D) has been targeted in the
design of most kinase inhibitors. A lot of research has been
focused on the structural modification of N-methyl-4-picoli-
namide moiety in the sorafenib scaffold in order to enhance
the antitumor activity, especially against melanoma, and to
improve the physiological property [8, 12–16].
Not only were the sulfonamide derivatives known for
their antibacterial activity, but they also emerged as an im-
portant class of anticancer agents which interact with a wide
range of different cellular targets [17, 18]. The sulfonamide
moiety has attracted our considerable attention as a new
hinge-binding group instead of N-methyl-4-picolinamide
(
Sorafenib, a diaryl urea small molecule inhibitor of several
kinases involved in tumor proliferation and tumor angio-
genesis including Raf, VEGFR and PDGFR [1], was ap-
proved by the U.S. Food and Drug Administration (FDA)
for the treatment of advanced renal cell carcinoma (RCC) [1]
and unresectable hepatocellular carcinoma (HCC) [2] in
[
2
005 and 2007 respectively. Due to its advantage of mul-
ti-mechanism, broad-spectrum anticancer activity and good
tolerability in combination trials, there remains great inter-
est in designing and developing novel diaryl urea com-
pounds with more potent antitumor activity [3–8].
The crystal structure of sorafenib in complex with B-raf
(
PDB:1UWH) served as a surrogate for structure-based op-
timization [9]. It has been shown that the urea moiety is
highly conservative (fragment B) shared by most type 2
kinase inhibitors. The substituted phenyl ring (fragment A)
contributes mainly to the kinase selectivity of sorafenib, the
(fragment D) in terms of novelty, and chemical modifica-
tion accessibility.
Our initial effort was to design novel diphenyl urea de-
rivatives containing the sulfonamide moiety (4a–i) based on
the structural modification of sorafenib, with the aim to ob-
tain more potent antitumor agents. Literature research re-
*
Corresponding authors (email: chxg@imm.ac.cn; joyce@imm.ac.cn)
©
Science China Press and Springer-Verlag Berlin Heidelberg 2013
chem.scichina.com www.springerlink.com

2
Luo C, et al. Sci China Chem January (2013) Vol.56 No.1
vealed that the replacement of phenyl ring (fragment C)
with a large naphthyl ring could bring favorable hydropho-
bic binding interaction [4, 11]. Therefore, the benefit of the
naphthyl system prompted us to design a series of phenyl-
naphthyl urea derivatives (10a–i), not only to improve the
antitumor activity but also to understand the effect of the mo-
lecular size on the activity by comparison with the diphenyl
urea series. Finally, the amino group as part of the sulfona-
mide moiety was selected from -methylbenzylamine,
cyclic alkyl amine including N- or O- containing heterocy-
clic amine in order to evaluate their impact on activity.
Herein, we report the discovery of a new series of diaryl
urea derivatives containing the sulfonamide moiety (Figure
was outlined in Scheme 1. Condensation of 4-nitro-ben-
zenesulfonyl chloride (1) with corresponding amines in the
presence of triethylamine, followed by catalytic hydrogena-
tion with 10% Pd/C to give 3a–c in the yields of 83%–92%.
Finally, condensation of 3a–c with corresponding aryl iso-
cyanates afforded the desired diphenyl urea derivatives 4a–i
[19].
The synthesis of phenyl-naphthyl urea sulfonamide de-
rivatives 10a–i was outlined in Scheme 2. Protection of
6-aminonaphthalene-2-sulfonic acid (5) by benzyl chlo-
roformate (Cbz-Cl) in the presence of sodium carbonate
gave N-Cbz protected compounds (6), then sulfonic acid
was transferred to sulfonyl chloride (7) in the presence of
thionyl chloride, followed by condensation with corre-
sponding amine in the presence of triethylamine to obtain
compounds 8a–c. Then Cbz group of the amines 8a–c was
removed by catalytic hydrogenation with 10% Pd/C to give
9a–c. Finally, condensation of 9a–c with corresponding aryl
isocyanates afforded the desired phenyl-naphthyl urea de-
rivatives 10a–i. The chemical structures of the compounds
1
) based on the structural features of sorafenib with the in-
tent of improving the antitumor activity. All target com-
pounds were evaluated for their in vitro antitumor activity
against five cancer cell lines, including human breast cancer
(
MX-1), human melanoma cancer (A375), human liver
cancer (HepG2), human kidney cancer (Ketr3) and human
colon cancer (HT-29) cell lines, using the standard 3-(4,
1
13
5
-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
were confirmed by H NMR, C NMR and HR-MS and the
results were presented in the experimental section.
(MTT) assay.
2
.2 Biological evaluation
2
Results and discussion
The in vitro inhibitory activity of target compounds 4a–i,
2
.1 Chemistry
1
0a–i against MX-1, A375, HepG2, Ketr3 and HT-29 cell
The synthesis of diphenyl urea sulfonamide derivatives 4a–i
lines was evaluated by MTT-based assay with sorafenib as
Figure 1 Structures of sorafenib and diaryl urea derivatives bearing sulfonamide moiety.
3 4 3 2
Scheme 1 Synthesis of compounds 4a–i. Reagents and conditions: i) NHR R , Et N/THF; ii) H , 10% Pd/C, THF/MeOH; iii) ArNCO, anhydrous THF.

Luo C, et al. Sci China Chem January (2013) Vol.56 No.1
3
Scheme 2 Synthesis of compounds 10a–i. Reagents and conditions: i) Cbz-Cl, Na
0% Pd/C, THF/MeOH; v) ArNCO, anhydrous THF.
2 3 2 2 3 4 3 2 2 2
CO , THF/H O; ii) SOCl , DMF; iii) NHR R , Et N, CH Cl ; iv) H ,
1
the positive control. The 50% inhibitory concentration (IC50
)
4e). Interestingly we were pleased to find that compounds
with 2,6-dimethylmorpholine sulfonamide moiety (10d, 10e)
showed significantly improved activity against A375,
HepG2 and Ketr3 cell lines with IC50 values around or be-
low 1 micromolar. It indicates that 2,6-dimethylmorpholine
could be a preferred group when choosing sulfonamide
moiety in the further structure modification. Furthermore,
the trend that the replacement of phenyl ring C with na-
phathyl system may benefit the antitumor activity, was con-
sistent with the previous structure-activity relationships
was defined as the concentration that reduced the absorb-
ance of the untreated wells by 50% compared to the vehicle
in the MTT assay.
As shown in Table 1, compounds 4a, 4d and 4g with the
same distal phenyl ring substituents 3-CF
similar potency (IC50 3.15–22.8 mol/L) versus sorafenib
IC50 5.52–14.4 mol/L) against MX-1, A375, HepG2 and
3
-4-Cl exhibited
(
Ketr3 cell lines, except HT-29 cell line. Interestingly, the
electron-withdrawing group CF of the distal phenyl A ring
3
(
[
SAR) results generated from sorafenib and its analogues
11]. It was worth noting that compound 10d demonstrated
in position 4 led to more potent inhibitors than that in posi-
tion 3, as exemplified by compound 4e versus compounds
significant activity against A375, HepG2 and Ketr3, which
was 5–20-fold more potent than sorafenib, and thereby
could become a valuable lead for further optimization. In
addition, the SAR of phenyl-naphthyl urea sulfonamide
derivatives needs further investigation.
4
b and 4h [4]. On the other hand, compounds with elec-
tron-donating group OCH on the 4-position in the phenyl
ring (4c, 4f and 4i) lost antitumor activity against five cell
lines completely with IC values over 50 mol/L. Moreover,
sulfonamides with a large substituent on nitrogen, such as 4d
with -methylbenzyl and 4g with 4-methylpi- peridine
3
5
0
displayed significantly improved activity compared to 4a
containing the cyclobutyl group.
3 Conclusion
The preliminary promising results of diphenyl urea sul-
fonamide derivatives prompted us to investigate the impact
of modification on the fragment C using the naphathyl to
replace the phenyl (10a–i). In addition, several heterocyclic
alkyls containing N or O such as 2,6-dimethylmorpholine
and 4-methylpiperazine were introduced into sulfonamide
moiety to enhance the inhibitory activity [13]. The effect of
substituents on the distal phenyl ring was also explored. Not
surprisingly, a methoxy group on fragment A (10c, 10f, 10i)
drastically decreased the activity (IC50 > 50 mol/L), simi-
lar to that in the diphenyl urea system. Bearing an elec-
tron-withdrawing group on fragment A, compounds with
In summary, a series of novel scaffold, diaryl urea deriva-
tives bearing sulfonamide moiety (4a–i, 10a–i) have been
synthesized based on the structural features of sorafenib and
their anti-proliferative activity was evaluated against human
cancer cell lines MX-1, A375, HepG2, Ketr3 and HT-29. The
most potential compound 10d in the 2,6-naphthyl series with
a large polar sulfonamide fragment exhibited improved ac-
tivity against A375, HepG2 and Ketr3 cell lines compared
to the reference compound sorafenib. Compound 10d could
become a valuable lead for further optimization. These re-
sults suggest that development of diaryl urea sulfonamide
scaffold is a very promising approach leading to more po-
tent antitumor agents. The SAR of phenyl-naphthyl urea
sulfonamide derivatives will be investigated in due course.
-methylbenzyl sulfonamide moiety (10a, 10b) displayed
similar activity compared to the phenyl counterparts (4d,

4
Luo C, et al. Sci China Chem January (2013) Vol.56 No.1
Table 1 Structures and inhibitory activity of target compounds against MX-1, A375, HepG2, Ketr3 and HT-29 cancer cell lines in vitro
IC50 (µmol/L)
Compd.
R
1
R
2
3 4
NR R
MX-1
22.8
A375
15.2
HepG2
Ketre3
15.3
HT-29
23.5
*
*
*
4
a
CF
CF
H
3
Cl
H
HN
12.5
4
b
3
HN
HN
>50
>50
12.1
>50
12.6
>50
>50
>50
>50
>50
4
c
OCH
3
3
3
4
d
CF
3
Cl
14.4
>50
10.8
13.4
7.48
23.0
7.21
11.6
22.9
21.9
*
*
*
HN
HN
HN
4
e
H
CF
3
4
f
H
CF
CF
H
OCH
Cl
>50
11.1
>50
>50
>50
11.5
>50
>50
>50
13.5
>50
>50
>50
3.15
>50
>50
>50
11.1
24.9
>50
4
g
3
3
*
*
*
N
N
N
4
h
H
4
i
OCH
1
0a
0b
CF
CF
H
3
3
Cl
H
13.6
12.8
>50
12.5
12.3
>50
10.3
12.5
>50
13.5
9.44
>50
13.7
12.9
>50
*
HN
HN
HN
1
*
*
1
0c
OCH
3
1
0d
CF
CF
H
3
3
Cl
H
*
*
*
N
O
9.31
21.4
>50
0.97
4.45
>50
0.85
4.71
>50
0.65
4.60
>50
9.01
21.6
>50
1
0e
N
N
O
O
1
0f
OCH
3
1
0g
0h
CF
CF
H
3
3
Cl
H
*
*
*
N
N
N
N
14.1
14.0
13.7
17.1
16.8
17.3
>50
17.0
25.6
1
N
N
23.2
1
0i
OCH
3
>50
>50
>50
>50
>50
Sorafenib
12.1
5.52
14.4
12.6
2.72
4
Experimental
NMR spectra were obtained on Mercury-300, 400 MHz
1
13
spectrometers (300 MHz for H NMR and 100 MHz for C
NMR) with tetramethylsilane (TMS) as the internal stand-
ard. High-resolution mass spectra (HR-MS) were taken in
electrospray ionization (ESI) mode on an Agilent 1100 se-
4
.1 Materials and apparatus
Melting points were determined with a Yanaco MP-J3 mi-
cro melting point apparatus and were uncorrected. The

Luo C, et al. Sci China Chem January (2013) Vol.56 No.1
5
ries LC/MSD mass spectrometer. All reagents and solvents
were purchased from commercial sources unless otherwise
indicated. Anhydrous THF was distilled from Na/benzo-
ArH), 7.62 (d, 2 H, J = 9 Hz, ArH), 7.53 (m, 2 H, ArH),
7.33 (d, 1 H, J = 7.8 Hz, ArH), 3.58 (m, 1 H, NHCH),
1.87–1.46 (m, 6 H, CH CH CH ); C-NMR (100 MHz,
2 2 2
13
phenone under a N
2
atmosphere. TLC was carried out on
DMSO-d )  152.23, 142.98, 140.17, 134.26, 129.96 (2 C),
6
silica gel plates (GF254) with visualization of components by
UV light (254 nm). Column chromatography was carried
out on silica gel (200-300 mesh).
129.69, 127.65 (2 C), 122.08 (q, J = 30.7 Hz), 118.45,
117.84 (2 C), 114.38, 47.53, 30.54 (2 C), 14.50; HR-MS
+
+
(ESI-TOF ): m/z [M + H] calcd for C H F N O S:
1
8
19
3
3
3
4
14.1094; found: 414.1097.
4
.2 General procedures
N-Cyclobutyl-{4-[3-(4-methoxyphenyl)urea]phenyl}sulfona-
mide (4c)
N-Cyclobutyl-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)urea]
phenyl}sulfonamide (4a)
Compound 4c was prepared from 1 in a manner similar to
that described for compound 4a with a yield of 67.3%. Mp:
To a solution of cyclobutylamine (1.70 mL, 20 mmol) in
1
2
14–215 °C; H-NMR (300 MHz, DMSO-d
6
)  9.00 (s, 1 H,
3
THF (20 mL) and Et N (4 mL, 25 mmol) was added
NHCONH), 8.59 (s, 1 H, NHCONH), 7.75 (d, 1 H, J = 9
Hz, SO NH), 7.65 (d, 2 H, J = 8.4 Hz, ArH), 7.58 (d, 2 H, J
8.7 Hz, ArH), 7.35 (d, 2 H, J = 8.7 Hz, ArH), 6.87 (d, 2 H,
J = 9 Hz, ArH), 3.71 (s, 3 H, OCH ), 3.58 (m, 1 H, NHCH),
.87–1.46 (m, 6 H, CH CH CH ); C-NMR (100 MHz,
DMSO-d )  154.74, 152.29, 143.30, 135.58, 133.90, 127.65
4
-nitrobenzenesulfonylchloride (1) (5.54 g, 25 mmol) in
THF (20 mL) by dropwise under argon protection at 0 °C.
Then the reaction mixture was stirred at room temperature
for 2 h. The mixture was poured into water, and extracted
with EtOAc, then the organic layer was washed with brine,
2
=
3
13
1
2
2
2
dried over MgSO
4
, filtered and concentrated. The residue
6
(
4
2 C), 120.30, 120.23, 117.54 (2 C), 115.43, 115.21, 55.16,
was purified by silica gel column chromatography (Petro-
leum ether/EtOAc (v/v) = 2:1) under reduced pressure
to give 4.84 g 2a as an off-white solid with a yield of
+
7.52, 30.53 (2 C), 14.50; HR-MS (ESI-TOF ): m/z [M +
+
22 3 4
H] calcd for C18H N O S: 376.1326; found: 376.1317.
9
4.4%.
To a solution of 2a (4.84 g, 18.9 mmol) in THF (25 mL)
N-[(+/)-1-Phenylethyl]-{4-[3-(4-chloro-3-(trifluoromethyl)
phenyl)urea]phenyl}sulfonamide (4d)
was added a mixture of 10% Pd/C (0.48 g) in methanol (2
mL), hydrogenated under medium pressure for 4 h. Then
the mixture was filtered and concentrated. The residue was
washed with hexane to give 4.21 g 3a as an off-white solid
with a yield of 98.4%.
To a solution of (+/)-1-phenylethylamine (2.82 mL, 22
mmoL) in THF (20 mL) and Et N (4.16 mL, 30 mmoL) was
3
added 4-nitrobenzenesulfonylchloride (1) (4.44 g, 20 mmol)
in THF (20 mL) by dropwise under argon protection at 0 °C.
Then the reaction mixture was stirred at room temperature
for 3 h. The mixture was poured into water, and extracted
with EtOAc, then the organic layer was washed with brine,
To a solution of 3a (1.0 eq.) in anhydrous THF (5 mL)
was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate
(
1.1 eq.) in anhydrous THF (5 mL) by dropwise under argon
protection at 0 °C. Then the mixture was stirred for about 20 h
at room temperature. The mixture was concentrated in vacuo
and the residue was recrystallized in MeOH to give 0.17 g
dried over MgSO , filtered and concentrated. The residue
was washed with petroleum ether to give 5.89 g 2b as a
light yellow solid with a yield of 96.1%.
4
of 4a as a white solid with a yield of 54.8%. Mp:
To a solution of 2b (5.85 g, 19.1 mmol) in THF (20 mL)
was added a mixture of 10% Pd/C (0.57 g) in methanol (2
mL), hydrogenated under medium pressure for 4 h. Then
the mixture was filtered and concentrated. The residue was
washed with petroleum ether to give 5.09 g 3b as a white
solid with a yield of 96.4%.
1
2
29–231 °C; H-NMR (300 MHz, DMSO-d
6
)  9.97 (s, 2 H,
NHCONH), 8.11 (s, 1 H, ArH), 7.78 (d, 1 H, J = 8.7 Hz,
SO NH), 7.65 (m, 6 H, ArH), 3.58 (m, 1 H, NHCH),
2
1
3
1
.87–1.39 (m, 6 H, CH
2 2 2
CH CH ); C-NMR (100 MHz,
DMSO-d ) δ 152.15, 142.83, 138.95, 134.41, 132.03 (2 C),
6
1
1
27.64, 126.56 (2 C), 123.31 (2 C), 122.70 (q, J = 30.0 Hz),
To a solution of 3b (1.0 eq.) in anhydrous THF (5 mL)
was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate
(1.1 eq.) in anhydrous THF (5 mL) by dropwise under argon
protection at 0 °C. Then the mixture was stirred for about 20 h
at room temperature. The mixture was concentrated in vacuo
and purified by silica gel column chromatography (Petro-
leum ether/THF (v/v) = 3:2) to give 0.25g 4d as a white
17.96 (2 C), 117.01, 47.52, 30.52 (2 C), 14.49; HR-MS
+
+
(
ESI-TOF ): m/z [M + H] calcd for C H ClF N O S:
18 18 3 3 3
4
48.0704; found: 448.0691.
N-Cyclobutyl-{4-[3-(3-(trifluoromethyl)phenyl)urea]phenyl}
sulfonamide (4b)
1
Compound 4b was prepared from 1 in a manner similar to
solid with a yield of 71.7%. Mp: 226–227 °C; H-NMR
that described for compound 4a with a yield of 63.0%. Mp:
(300 MHz, DMSO-d )  9.25 (s, 1 H, NHCONH), 9.21 (s,
1 H, NHCONH), 8.11 (s, 1 H, ArH), 8.04 (d, 1 H, J = 8.1
6
1
2
11–212 °C; H-NMR (300 MHz, DMSO-d
6
)  9.26 (s, 1 H,
NH),
.78 (d, 1 H, J = 8.7 Hz, ArH), 7.68 (d, 2 H, J = 9.3 Hz,
NHCONH), 9.21 (s, 1 H, NHCONH), 8.01 (s, 1 H, SO
2
Hz, SO
2
NH), 7.66–7.51 (m, 6 H, ArH), 7.21–7.12 (m, 5 H,
), 1.18 (d, 3 H, J = 6.6 Hz,
7
ArH), 4.33 (m, 1 H, NHCHCH
3

6
Luo C, et al. Sci China Chem January (2013) Vol.56 No.1
1
3
CH
1
1
3
); C-NMR (100 MHz, DMSO-d
6
)  152.12, 143.56,
mL), hydrogenated under medium pressure for 4 h. Then
the mixture was filtered and concentrated. The residue was
washed with hexane to give 0.98 g 3c as an off-white solid
with a yield of 98.9%.
To a solution of 3c (1.0 eq.) in anhydrous THF (5 mL)
was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate
42.59, 138.96, 134.38, 132.02, 128.04 (2 C), 127.59 (2 C),
26.87 (2 C), 126.67 (2 C), 126.57, 126.01 (2 C), 122.89 (q,
J = 82.2 Hz), 117.74 (2 C), 52.69, 23.46; HR-MS (ESI-
TOF ): m/z [M + H] calcd for C22
found: 498.0863.
+
+
H
20ClF
3
N
3
O
3
S: 498.0861;
(
1.1 eq.) in anhydrous THF (5 mL) by dropwise under argon
N-[(+/-)-1-Phenylethyl]-{4-[3-(4-(trifluoromethyl)phenyl)
urea]phenyl}sulfonamide (4e)
protection at 0 °C. Then the mixture was stirred for about 20 h
at room temperature. The mixture was concentrated in vacuo
and purified by silica gel column chromatography (Petro-
leum ether/EtOAc (v/v) = 2:1) to give 0.14 g 4g as a light
Compound 4e was prepared from 1 in a manner similar to
that described for compound 4d with a yield of 81.0%. Mp:
1
yellow solid with a yield of 49.1%. Mp: 179–181 °C;
2
26–228 °C; H-NMR (300 MHz, DMSO-d )  9.20 (s, 1 H,
6
1
H-NMR (300 MHz, DMSO-d
6
)  9.35 (s, 1 H, NHCONH),
.29 (s, 1 H, NHCONH), 8.10 (s, 1 H, ArH), 7.70–7.62 (m,
H, ArH), 3.56 (d, 2 H, J = 11.4 Hz, NCH ), 2.15 (t, 2 H,
), 1.63 (d, 2 H, J = 11.7 Hz, CHCH ),
1.24 (brs, H, CHCH ), 1.11 (m, 2 H, CHCH ), 0.84 (d, 3 H,
NHCONH), 9.17 (s, 1 H, NHCONH), 8.04 (d, 1 H, J = 7.8
Hz, SO NH), 7.65 (m, 4 H, ArH), 7.60 (d, 2 H, J = 9 Hz,
ArH), 7.53 (d, 2 H, J = 8.7 Hz, ArH), 7.21–7.12 (m, 5 H,
ArH), 4.31 (m, 1 H, NHCHCH ), 1.18 (d, 3 H, J = 6.9 Hz,
); C-NMR (100 MHz, DMSO-d )  151.99, 143.57,
9
6
2
2
J = 11.4 Hz, NCH
2
2
3
1
13
3
2
CH
3
6
13
J = 6.3 Hz, CH
3
); C-NMR (100 MHz, DMSO-d
6
)  152.13,
1
1
1
43.06, 142.68, 134.29, 128.05 (2 C), 127.62 (2 C), 126.67,
1
1
1
43.52, 138.90, 132.04, 128.70 (2 C), 128.15, 126.87,
26.57, 123.06 (q, J = 118.7 Hz), 118.08 (2 C), 117.07,
26.12, 126.08 (2 C), 126.01 (2 C), 122.65 (q, J = 82.2 Hz),
+
18.09 (2 C), 117.61 (2 C), 52.69, 23.46; HR-MS (ESI-TOF ):
+
17.02, 46.04 (2 C), 32.81 (2 C), 29.29, 21.28; HR-MS
m/z [M + H] calcd for C22
H
21
F
3
N
3
O
3
S: 464.1250; found:
+
+
(
3 3 3
ESI-TOF ): m/z [M + H] calcd for C20H22ClF N O S:
4
64.1247.
4
76.1017; found: 476.1015.
N-[(+/)-1-Phenylethyl]-{4-[3-(4-methoxyphenyl)urea]phenyl}
sulfonamide (4f)
4
-Methyl-1-{4-[3-(3-(trifluoromethyl)phenyl)urea]phenyl}
sulfonyl piperidine (4h)
Compound 4f was prepared from 1 in a manner similar to
Compound 4h was prepared from 1 in a manner similar to
that described for compound 4g with a yield of 31.3%. Mp:
1
that described for compound 4d with a yield of 75.0%. Mp:
1
2
17–218 °C; H-NMR (300 MHz, DMSO-d )  8.95 (s, 1 H,
6
1
75–176 °C; H-NMR (300 MHz, DMSO-d
6
)  9.32 (s, 1 H,
NHCONH), 8.57 (s, 1 H, NHCONH), 8.00 (d, 1 H, J = 8.1
NHCONH), 9.20 (s, 1 H, NHCONH), 8.01 (s, 1 H, ArH),
Hz, SO NH), 7.58 (d, 2 H, J = 8.7 Hz, ArH), 7.50 (d, 2 H, J =
2
7
7
2
.69 (d, 2 H, J = 9 Hz, ArH), 7.63 (d, 2 H, J = 9.3 Hz, ArH),
9
5
Hz, ArH), 7.35 (d, 2 H, J = 8.7 Hz, ArH), 7.21–7.13 (m,
H, ArH), 6.87 (d, 2 H, J = 9.3 Hz, ArH), 4.29 (m, 1 H,
.54 (m, 2 H, ArH), 7.34 (d, 1 H, J = 7.8 Hz, ArH), 3.56 (d,
H, J = 11.4 Hz, NCH ), 2.16 (t, 2 H, J = 10.5 Hz, NCH ),
NHCHCH
3
), 3.71 (s, 3 H, OCH
3
), 1.18 (d, 3 H, J = 6.9 Hz,
2
2
1
13
1.63 (d, 2 H, J = 10.8 Hz, CHCH ), 1.27 (brs, H, CHCH ),
2
3
CH3); C-NMR (100 MHz, DMSO-d )  154.71, 152.32,
6
1
.14 (m, 2 H, CHCH
2
3
), 0.84 (d, 3 H, J = 6.3 Hz, CH );
1
1
43.63, 143.29, 133.60, 132.22, 128.04 (2 C), 127.59 (2 C),
26.66, 126.01 (2 C), 120.26 (2 C), 117.18 (2 C), 114.00 (2
13
C-NMR (100 MHz, DMSO-d )  152.21, 143.67, 140.13,
6
+
+
1
1
2
29.96, 128.70 (2 C), 127.98 (2 C), 122.12 (q, J = 82.7 Hz),
C), 55.16, 52.65, 23.45; MS (ESI-TOF ): m/z [M + H]
calcd for C22 S: 426.1482; found: 426.1485.
18.52 (2 C), 117.94 (2 C), 114.40, 46.04 (2 C), 32.81 (2 C),
24 3 4
H N O
+
+
9.28, 21.29; HR-MS (ESI-TOF ): m/z [M + H] calcd for
4
-Methyl-1-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)urea]
phenyl}sulfonyl piperidine (4g)
To a solution of 4-methylpiperidine (0.60 mL, 5 mmol) in
THF (20 mL) and Et N (0.77 mL, 5.5 mmol) was added
-nitrobenzenesulfonylchloride (1) (1.15g, 5.2 mmol) in
C H F N O S: 442.1407; found: 442.1403.
20 23 3 3 3
4
-Methyl-1-{4-[3-(4-methoxyphenyl)urea]phenyl}sulfonyl
piperidine (4i)
3
4
Compound 4i was prepared from 1 in a manner similar to
THF (20 mL) by dropwise under argon protection at 0 °C.
Then the reaction mixture was stirred at room temperature
for 2 h. The mixture was poured into water, and extracted
with EtOAc, then the organic layer was washed with brine,
that described for compound 4g with a yield of 73.4%. Mp:
1
189–190°C; H-NMR (300 MHz, DMSO-d
6
)  9.08 (s, 1 H,
NHCONH), 8.60 (s, 1 H, NHCONH), 7.65 (d, 2 H, J = 8.7
Hz, ArH), 7.60 (d, 2 H, J = 9 Hz, ArH), 7.35 (d, 2 H, J =
8.4 Hz, ArH), 6.87 (d, 2 H, J = 9 Hz, ArH), 3.71 (s, 3 H,
4
dried over MgSO , filtered and concentrated. The residue
was purified by silica gel column chromatography (Petro-
leum ether/THF (v/v) = 3:2) to give 1.20 g 2c as a yellow
solid with a yield of 84.4%.
To a solution of 2c (1.12 g, 3.9 mmol) in THF (25 mL)
was added a mixture of 10% Pd/C (0.11 g) in methanol (2
OCH
12.3 Hz, NCH
1 H, CHCH ), 1.11 (m, 2 H, CHCH
3
), 3.55 (d, 2 H, J = 11.7 Hz, NCH
), 1.63 (d, 2 H, J = 12 Hz, CHCH
), 0.84 (d, 3 H, J = 6.3
); C-NMR (100 MHz, DMSO-d )  154.76, 152.30,
144.19, 132.14, 128.70 (2 C), 127.33, 120.32 (2 C), 117.48
2
), 2.15 (t, 2 H, J =
2
2
), 1.27 (m,
3
2
13
Hz, CH
3
6

Luo C, et al. Sci China Chem January (2013) Vol.56 No.1
7
(
2
2 C), 114.00 (2 C), 55.16, 46.04 (2 C), 32.81 (2 C), 29.29,
1.30; HR-MS (ESI-TOF ): m/z [M + H] calcd for
S: 404.1639; found: 404.1638.
NHCONH), 8.22–8.18 (m, 3 H, ArH), 8.08 (s, 1 H, SO
7.97 (d, 1 H, J = 9 Hz, ArH), 7.88 (d, 1 H, J = 8.7 Hz, ArH),
7.66–7.50 (m, 4 H, ArH), 7.34 (d, 1 H, J = 7.8 Hz, ArH),
2
NH),
+
+
20 26 3 4
C H N O
7
.20–7.02 (m, 5 H, ArH), 4.38 (m, 1 H, NHCH), 1.18 (d, 3
+
+
N-[(+/)-1-Phenylethyl]-{6-[3-(4-chloro-3-(trifluoromethyl)
phenyl)urea]naphthalene-2-yl}sulfonamide (10a)
H, J = 6.6 Hz, CH ); HR-MS (ESI-TOF ): m/z [M + H]
calcd for C H F N O S: 514.1407; found: 514.1390.
3
26
23
3
3
3
To an aqueous solution of 6-aminonaphthalene-2-sulfonic
acid (5) (2.23 g, 10 mmol) and sodium carbonate (2.12 g, 20
mmol) was added THF (20 mL), then benzyl chloroformate
N-[(+/-)-1-Phenylethyl]-{6-[3-(4-methoxyphenyl)urea]na-
phthalen-2-yl}sulfonamide (10c)
(
4
Cbz-Cl) (1.57 mL, 11 mmol) was added by dropwise at
0°C. The mixture was stirred at room temperature for 2 h
Compound 10c was prepared from 5 in a manner similar to
that described for compound 10a with a yield of 63.2%. Mp:
1
then concentrated under reduced pressure, acidized with 1N
HCl, filtered and washed with water to give 2.95 g com-
pound 6 as a white solid with a yield of 82.4%.
207–209 °C; H-NMR (300 MHz, DMSO-d
6
)  8.99 (s, 1 H,
NHCONH), 8.62 (s, 1 H, NHCONH), 8.19 (d, 1 H, J = 8.1 Hz,
SO NH), 8.15 (s, 2 H, ArH), 7.94 (d, 1 H, J = 9 Hz, ArH),
2
To a solution of 6 (1.79 g, 5 mmol) in DMF (20 mL) was
added thionyl chloride (0.54 mL, 7.5 mmol), stirred at room
temperature for 4 h. The mixture was poured into ice-water,
extracted with dichloromethane, then the organic layer was
7.84 (d, 1 H, J = 8.7 Hz, ArH), 7.63 (d, 1 H, J = 8.4 Hz, ArH),
7.56 (d, 1 H, J = 7.8 Hz, ArH), 7.39 (d, 2 H, J = 8.7 Hz,
ArH), 7.20–7.02 (m, 5 H, ArH), 6.88 (d, 2 H, J = 8.7 Hz,
ArH), 4.37 (m, 1 H, NHCH), 3.72 (s, 3 H, OCH ), 1.18 (d, 3
3
+
+
washed with brine, dried over MgSO
4
, filtered and concen-
H, J = 6.9 Hz, CH ); HR-MS (ESI-TOF ): m/z [M + H]
3
trated. The residue was resolved in dichloromethane with
triethylamine (1.4 mL, 10 mmol) then added (+/)-1-phen-
ylethylamine (0.65 mL, 5 mmol) by dropwise at 0 °C. The
mixture was stirred at room temperature for 6 h then con-
centrated under reduced pressure. The residue was purified
calcd for C H N O S: 476.1639; found: 476.1624.
26
26
3
4
2,6-Dimethyl-4-{6-[3-(4-chloro-3-(trifluoromethyl)phenyl)
urea]naphthalen-2-yl}sulfonyl morpholine (10d)
To a solution of 6 (1.79 g, 5 mmol) in DMF (20 mL) was
added thionyl chloride (0.54 mL, 7.5 mmol), stirred at room
temperature for 4 h. The mixture was poured into ice-water,
extracted with dichloromethane, then the organic layer was
by silica gel column chromatography (CH
v/v/v) = 100:10:1) to give 1.66 g 8a as a white solid with a
yield of 72.1%.
2 2 3
Cl /MeOH/Et N
(
To a solution of 8a (0.46 g, 1 mmol) in THF (15 mL)
was added a mixture of 10% Pd/C (0.05 g) in methanol (2
mL), hydrogenated under atmosphere for 4 h. Then the
mixture was filtered and concentrated under reduced pres-
sure to give 0.32 g 9a as an off-white solid with a yield of
washed with brine, dried over MgSO , filtered and concen-
4
trated. The residue was resolved in dichloromethane with
triethylamine (0.7 mL, 5 mmol) then added 2,6-dimethyl-
morpholine (0.62 mL, 5 mmol) by dropwise at 0 °C. The
mixture was stirred at room temperature for 4 h then con-
centrated under reduced pressure. The residue was purified
by silica gel column chromatography (CH Cl /MeOH/Et N
9
8.1%.
To a solution of 9a (1.0 eq.) in anhydrous THF (3 mL)
was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate
1.1 eq.) in anhydrous THF (5 mL) by dropwise under argon
2
2
3
(
v/v/v) = 50:5:1) to give 0.89 g 8b as a white solid with a
(
yield of 39.2%.
protection at 0 °C. Then the mixture was stirred for about 20 h
at room temperature. The mixture was concentrated in vacuo
and purified by silica gel column chromatography (petro-
leum ether/EtOAc (v/v) = 1:1) to give 0.10 g 10a as a white
To a solution of 8b (0.90 g, 2 mmol) in THF (20 mL)
was added a mixture of 10% Pd/C (0.09 g) in methanol (2
mL), hydrogenated under atmosphere for 6 h. Then the
mixture was filtered and concentrated under reduced pres-
sure to give 0.64 g 9b as an off-white solid with a yield of
99.3%.
1
solid with a yield of 95.4%. Mp: 228–229 °C; H-NMR
(
300 MHz, DMSO-d )  9.32 (s, 1 H, NHCONH), 9.26 (s, 1
6
1
H, NHCONH), 8.24–8.20 (m, 3 H, ArH), 8.17 (d, H, J =
.9 Hz, SO NH), 7.98 (d, 1 H, J = 9 Hz, ArH), 7.88 (d, 1 H,
To a solution of 9b (1.0 eq.) in anhydrous THF (3 mL)
was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate
(1.1 eq.) in anhydrous THF (5 mL) by dropwise under argon
protection at 0 °C. Then the mixture was stirred for about 20 h
at room temperature. The mixture was concentrated in vacuo
and purified by silica gel column chromatography (petro-
leum ether/THF (v/v) = 1:1) to give 0.11 g 10d as an
off-white solid with a yield of 82.2%. Mp: 90–92 °C;
7
2
J = 9 Hz, ArH), 7.68–7.56 (m, 4 H, ArH), 7.20–7.02 (m, 5 H,
ArH), 4.37 (m, 1 H, NHCH), 1.18 (d, 3 H, J = 7.2 Hz, CH );
3
+
+
HR-MS (ESI-TOF ): m/z [M
+
H]
calcd for
C H ClF N O S: 548.1017; found: 548.0990.
2
6
22
3
3
3
N-[(+/)-1-Phenylethyl]-{6-[3-(3-(trifluoromethyl)phenyl)
urea]naphthalen-2-yl}sulfonamide (10b)
1
H-NMR (300 MHz, DMSO-d )  9.34 (d, 2 H, J = 3.3 Hz,
6
Compound 10b was prepared from 5 in a manner similar to
NHCONH), 8.32 (d, 2 H, J = 7.5 Hz, ArH), 8.17 (brs, 1 H,
that described for compound 10a with a yield of 93.5%. Mp:
ArH), 8.13 (brs, 1 H, ArH), 8.04 (d, 1 H, J = 9 Hz, ArH),
1
7
2
.65 (m, 4 H, ArH), 4.03–3.55 (m, 3 H, CHCH ), 2.64 (m,
1
75–178 °C; H-NMR (300 MHz, DMSO-d )  9.19 (s, 2 H,
6

8
Luo C, et al. Sci China Chem January (2013) Vol.56 No.1
1
CH
C
H, CHCH
); HR-MS (ESI-TOF ): m/z [M + H] calcd for
S: 542.1123; found: 542.1097.
3
), 1.88 (m, 2 H, NCH
2
), 1.13–1.01 (m, 6 H,
protection at 0 °C. Then the mixture was stirred for about 20 h
at room temperature. The mixture was concentrated in vacuo
and purified by silica gel column chromatography (CH
Cl
+
+
3
24
H
24ClF
3
N
3
O
4
2
2
/
MeOH (v/v) = 50:1) to give 0.10 g 10g as an off-white solid
with a yield of 65.2%. Mp: 208–210 °C; H-NMR (300
1
2
, 6-Dimethyl-4-{6-[3-(3-(trifluoromethyl)phenyl)urea]na-
phthalen-2-yl}sulfonyl morpholine (10e)
MHz, DMSO-d )  9.34 (s, 1 H, NHCONH), 9.32 (s, 1 H,
6
Compound 10e was prepared from 5 in a manner similar to
that described for compound 10d with a yield of 73.7%. Mp:
1
NHCONH), 8.29 (d, 2 H, J = 8.1 Hz, ArH), 8.17 (brs, 1 H,
ArH), 8.13 (d, 1 H, J = 9 Hz, ArH), 8.04 (d, 1 H, J = 9 Hz,
1
08–110 °C; H-NMR (300 MHz, DMSO-d
6
)  9.28 (s, 1 H,
ArH), 7.67–7.64 (m, 4 H, ArH), 2.93 (brs, 4 H, CH
CH ), 2.34 (brs, 4 H, CH N(CH )CH ), 2.11 (s, 3 H, CH
HR-MS (ESI-TOF ): m/z [M+H] calcd for C23
27.1126; found: 527.1130.
2 2
N(SO )
NHCONH), 9.23 (s, 1 H, NHCONH), 8.31 (brs, 2 H, ArH),
.14 (d, 1 H, J = 8 Hz, ArH), 8.08 (s, 1 H, ArH), 8.04 (d, 1 H,
J = 9 Hz, ArH), 7.68–7.51 (m, 4 H, ArH), 7.34 (d, 1 H, J =
2
2
3
2
3
);
S:
+
+
8
H
3 4 3
23ClF N O
5
7
1
.5 Hz, ArH), 4.00–3.55 (m, 3 H, CHCH
2
), 2.98–2.59 (m,
);
S:
H, CHCH ), 1.88 (m, 2 H, NCH ), 1.13–1.02 (m, 6 H, CH
3
2
+
3
1-Methyl-4-{6-[3-(3-(trifluoromethyl)phenyl)urea]naphtha-
len-2-yl} sulfonyl piperazine (10h)
+
25 3 3 4
HR-MS (ESI-TOF ): m/z [M + H] calcd for C24H F N O
5
08.1512; found: 508.1485.
Compound 10h was prepared from 5 in a manner similar to
that described for compound 10g with a yield of 30.4%. Mp:
2
2
, 6-Dimethyl-4-{6-[3-(4-methoxyphenyl)urea]naphthalene-
-yl}sulfonyl morpholine (10f)
1
9
8–101 °C; H-NMR (300 MHz, DMSO-d
6
)  9.46 (s, 2 H,
NHCONH), 8.30 (s, 2 H, ArH), 8.14–8.02 (m, 3 H, ArH),
Compound 10f was prepared from 5 in a manner similar to
that described for compound 10d with a yield of 88.9%. Mp:
2
H, NHCONH), 9.82 (s, 1 H, NHCONH), 8.28 (br, 2 H,
ArH), 8.08 (m, 1 H, ArH), 7.98 (d, 1 H, J = 9.3 Hz, ArH),
7
.67–7.53 (m, 4 H, ArH), 7.33 (d, 1 H, J = 6.9 Hz, ArH),
.94 (brs, 4 H, CH N(SO )CH ), 2.39 (brs, 4 H,
N(CH )CH ), 2.14 (s, 3 H, CH
m/z [M + H] calcd for C23
93.1524.
2
CH
2
2
2
1
+
32–234 °C; H-NMR (300 MHz, DMSO-d
6
)  10.31 (s, 1
2
3
2
3
); HR-MS (ESI-TOF ):
24 3 4 3
H F N O S: 493.1516; found:
+
4
7
2
.65 (m, 2 H, ArH), 7.43 (d, 2 H, J = 8.7 Hz, ArH), 6.87 (d,
H, J = 8.4 Hz, ArH), 3.98 (brs, 1 H, CHCH ), 3.72 (s, 3 H,
), 3.56 (m, 2 H, NCH ), 2.99–2.64 (m, 1 H, CHCH ),
.92 (m, 2 H, NCH ), 1.14–1.02 (m, 6 H, CH ); HR-MS
S:
1-Methyl-4-{6-[3-(4-methoxyphenyl)urea]naphthalen-2-yl}
sulfonyl piperazine (10i)
3
OCH
1
3
2
3
2
3
Compound 10i was prepared from 5 in a manner similar to
+
+
(
ESI-TOF ): m/z [M + H] calcd for C24
H
28
N
3
O
5
that described for compound 10g with a yield of 13.2%. Mp:
1
4
70.1744; found: 470.1723.
2
10–212 °C; H-NMR (300 MHz, DMSO-d
6
)  9.07 (s, 1 H,
NHCONH), 8.66 (s, 1 H, NHCONH), 8.28 (s, 1 H, ArH),
1
-Methyl-4-{6-[3-(4-chloro-3-(trifluoromethyl)phenyl)urea]
8
.24 (s, 1 H, ArH), 8.10 (d, 1 H, J = 9 Hz, ArH), 7.99 (d, 1
naphthalen-2-yl} sulfonyl piperazine (10g).
H, J = 8.7 Hz, ArH), 7.65–7.61 (m, 2 H, ArH), 7.39 (d, 2 H,
J = 8.7 Hz, ArH), 6.88 (d, 2 H, J = 9 Hz, ArH), 3.72 (s, 3 H,
OCH ), 2.93 (brs, 4 H, CH N(SO )CH ), 2.34 (brs, 4 H,
To a solution of 6 (0.54 g, 1.5 mmol) in DMF (10 mL) was
added thionyl chloride (0.36 mL, 5 mmol), stirred at room
temperature for 4 h. The mixture was poured into ice-water,
extracted with dichloromethane, then the organic layer was
washed with brine, dried over MgSO
4
, filtered and concen-
trated. The residue was resolved in dichloromethane with
triethylamine (0.21 mL, 1.7 mmol) and then added
3
2
2
2
+
CH N(CH )CH ), 2.11 (s, 3 H, CH ); HR-MS (ESI-TOF ):
m/z [M + H] calcd for C H N O S: 455.1748; found:
2
3
2
3
+
23
27
4
4
4
55.1746.
This work was financially supported by the National Science & Technology
Major Project (2009ZX09301-003-9-1).
1
0
-methylpiperazine (0.25 mL, 2.3 mmol) by dropwise at
°C. The mixture was stirred at room temperature for 4 h
then concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (CH
2
Cl /
MeOH (v/v) = 50:1) to give 0.52 g 8c as a white solid with a
yield of 78.9%.
1
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To a solution of 8c (0.52 g, 1.2 mmol) in THF (20 mL)
was added a mixture of 10% Pd/C (0.05 g) in methanol (2
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